Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Friedreich ataxia is an autosomal recessive neurological disorder caused by deficiency of the mitochondrial protein frataxin. Studies in patient cells, mouse knockout animals, and Saccharomyces cerevisiae models have suggested several hypotheses on the frataxin function, but the full physiology of frataxin in mitochondria has not been well established yet. We have characterized the genomic structure of frh-1, the Caenorhabditis elegans frataxin gene, and we have developed a transient knockdown model of C. elegans frataxin deficiency by RNA interference. frh-1(RNAi) worms show a consistent pleiotropic phenotype that includes slow growth, lethargic behavior, egg laying defects, reduced brood size, abnormal pharyngeal pumping, and altered defecation. Lifespan is significantly reduced, and worms have increased sensitivity to oxidative stress that, in turn, might explain the reduction of longevity of the worms. We also demonstrate synthetic genetic interaction between frh-1 and mev-1, the gene encoding the succinate dehydrogenase cytochrome b subunit of complex II in mitochondria, suggesting a possible role of the C. elegans frataxin in the electron transport chain; thus, the respiratory chain might be involved in the pathogenesis of the disease. We propose that this C. elegans model may be a useful biological tool for drug screening in Friedreich ataxia.
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PMID:Reduction of Caenorhabditis elegans frataxin increases sensitivity to oxidative stress, reduces lifespan, and causes lethality in a mitochondrial complex II mutant. 1667 53

We describe a 22-year-old male who developed severe hypoglycemia and lethargy during an acute illness at 4 months of age and subsequently grew and developed normally. At age 4 years he developed recurrent vomiting with mild hyperammonemia and dehydration requiring frequent hospitalizations. Glutaric aciduria Type II was suspected based upon biochemical findings and managed with cornstarch, carnitine and riboflavin supplements. He did not experience metabolic crises between ages 4-12 years. He experienced recurrent vomiting, mild hyperammonemia, and generalized weakness associated with acute illnesses and growth spurts. At age 18 years, he developed exercise intolerance and proximal muscle weakness leading to the identification of multiple acyl-CoA dehydrogenase and complex II/III deficiencies in both skeletal muscle and liver. Subsequent molecular characterization of the ETFDH gene revealed novel heterozygous mutations, p.G274X:c.820 G > T (exon 7) and p.P534L: c.1601 C > T (exon 12), the latter within the iron sulfur-cluster and predicted to affect ubiquinone reductase activity of ETFDH and the docking of ETF to ETFDH. Our case supports the concept of a structural interaction between ETFDH and other enzyme partners, and suggests that the conformational change upon ETF binding to ETFDH may play a key role in linking ETFDH to II/III super-complex formation.
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PMID:Novel ETF dehydrogenase mutations in a patient with mild glutaric aciduria type II and complex II-III deficiency in liver and muscle. 2108 98